Back when Kisame was a Kirigakureshinobi, he was instructed by his superior, Fuguki Suikazan, who was one of the Seven Ninja Swordsmen of the Mist, to serve as a bodyguard for Kiri's Cypher Division. Fuguki explicitly instructed him to do whatever was necessary to prevent their intelligence and secret codes from being leaked to any enemies. Whilst serving as their guard, Miru, a kunoichi from the Cypher Division, asked him to come and eat with the others, while the rest rebuffed him as a cold, callous individual. Shortly after, Kisame sensed the presence of enemies, who were revealed to be the Konoha Torture and Interrogation Force, led by Ibiki Morino. As Ibiki's team began capturing wounded Kiri-nin alive, Kisame dropped explosive tags near them or impaled them with his sword to kill them, in order to prevent Konoha from gathering intelligence. After being cornered on a cliff, Kisame killed the remaining three, including Miru, who had invited him to dinner after the mission earlier. With her dying breath, Miru asked why Kisame would do such a thing, and he explained that he had to do what was necessary to prevent an intelligence leak and that killing his comrades was his specialty. Kisame then jumped off the cliff to elude his own capture.

After reporting back to the village, Kisame discovered that Fuguki himself was leaking intelligence to their enemies, and killed his own master as a result, as it was his duty to kill fellow Kiri-nin in order to prevent leaks. After killing Fuguki, he took the swordsman's Samehada blade for his own. The murder was witnessed by Yagura, the Mizukage, who commended him for his efforts. Kisame, however, was wary as he believed that Yagura would simply kill him whenever his usefulness ended and mused that he had no sense of identity and wondered what he could do to achieve peace, instead of being stuck in a cycle of killing and deceit. To his surprise, a man emerged from behind Yagura and offered him the chance to join him as a comrade in order to obtain true peace. Kisame was shocked to see that the man possessed a Sharingan, which he had been using to control Yagura. Knowing that the shinobi in front of him must be quite formidable to not only control a kage but also a jinchūriki, as Yagura held the Three-Tails within him, Kisame demanded to know who the man was. The man declared himself to be none other than Madara Uchiha, and emerged from the shadows in order to show his face and prove it.

Wanting to protect his leader's identity, Kisame bites through his tongue, disrupting Aoba's technique, and proceeds to break out of his wooden restraints. Knowing he is too weak to fight the shinobi before him, Kisame traps himself inside his Water Prison Technique and recalls when he first met Itachi when they were partnered together, and how Itachi told him that a man does not know his true nature until he reaches the end of his life. Realising that he would rather die in order to protect the Akatsuki, Kisame summons three sharks and commits suicide by allowing the sharks to devour him. Naruto and Yamato are shocked, while Killer B confirms via Samehada that it is not a trick and that Kisame has actually died. Remembering Nagato and Konan, Naruto states that even in the Akatsuki, shinobi would sacrifice their lives in order to protect their comrades. Guy remarks that it is an honourable thing for a shinobi to do so, and declares that he would never forget Kisame so long as he lives.

Guy picks up the scroll containing the intel Kisame had gathered and opens it, only for it to be rigged. Naruto, Yamato, B, Guy, and Motoi are trapped in a water prison containing sharks while one of the sharks grabs the scroll and flees to the ocean.